Click chemistry has the potential to achieve functional group orthogonality, high yields, and/or other advantages in diverse applications, ranging from surface functionalization to drug delivery. However, the utility of a prototypical click reaction, the Cu-catalyzed alkyne-azide cycloaddition, can be hampered by the toxicity of copper salts towards living systems, their deleterious effects on redox-sensitive nanoparticles, or a combination thereof.
Strain-promoted alkyne-azide cycloaddition has been shown to address one or more of these limitations in bioorthogonal chemistry and surface chemistry. However, strain-activated cycloalkynes typically balance at the edge of instability, which can complicate synthesis and/or applications of such reactive molecules.
A ˜50-fold increase in reactivity of a difluorinated cyclooctyne (DIFO) relative to the parent cyclooctyne has been reported, which indicated that one or more other factors may be harnessed to supplement strain activation (Baskin, J. M. et al., Proc. Natl. Acad. Sci. U.S.A. 104, 16793 (2007)). It also has been reported that an endocyclic oxygen and nitrogen can be comparable in reactivity to DIFO (Ni, R. et al., Angew. Chem. Int. Ed. 54, 1190 (2015)).
Generally, the structural design of cycloalkynes in click chemistry include alkyne bending, sometimes amplified by one or more other external factors, such as ion sensing. Assembly of a cyclodecyne frame typically involves nucleophilic substitutions. The direct nucleophilic substitution approach to make smaller cycloalkynes usually is difficult due to the entropic and/or enthalpic penalty for the formation of strained rings. Previous success of cyclononyne synthesis has relied heavily on the Nicholas reaction to assemble the ring, an approach that requires two additional steps to protect and deprotect the alkyne (Ni, R. et al., Angew. Chem. Int. Ed. 54, 1190 (2015); and Kaneda, K. et al., Org. Lett. 19, 1096 (2017)).
Methods, including relatively facile methods, are desired that may introduce twisting along a cycloalkyne backbone that starts from the alkyne and passes through endocyclic C—X bonds to a biaryl core. Also desired are methods that demonstrate that the electronic energy stored in the twisted structure can be harvested in the click cycloaddition transition state (TS), and/or are capable of having a biaryl moiety introduce axial chirality due at least in part to the fact that restricted bond rotation may create atropisomers.